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SRI Magazine 2016

SRI Magazine 2016

A tapestry of clinical trials

High-impact findings: greater effectiveness, more precision, less harm and cost-conscious—this is what the cancer care of tomorrow looks like, emerging from the clinical trials of today

Masterpieces are not created in a day. Neither are better, kinder medical therapies, prized treasures in their own right. Researchers at Sunnybrook’s Odette Cancer Centre are leading the charge through clinical trials that seek to help patients with cancer live stronger, longer lives. Their mantra? Only the best is good enough.

Standard treatment for breast cancer involves surgery to remove the tumour and radiation to prevent recurrence. Adjuvant therapies are then typically given to reduce the odds of cancer coming back, and include chemotherapy and hormone, or endocrine, therapy. Endocrine therapy, which blocks estrogen from stimulating breast cancer cell growth, is relatively gentle and well-tolerated. Most patients with early-stage, hormone-sensitive breast cancer receive adjuvant endocrine therapy, some in combination with chemotherapy, the more toxic and gruelling of the two. “With chemotherapy, we’re probably treating a bunch of people that we don’t need to treat,” says Dr. Kathleen Pritchard, a medical oncologist and researcher at Sunnybrook Research Institute (SRI). “We need to know which patients are low enough risk that we don’t need to give them adjuvant chemotherapy.”

Concern for overtreatment is at the heart of the Trial Assigning Individualized Options for Treatment, or TAILORx study, which sought to determine whether the Oncotype DX Recurrence Score could predict which patients need additional chemotherapy. The test examines the activity of 21 genes in tumour tissue to generate a score between zero and 100—the higher the score, the greater the risk of the cancer returning. More than 10,000 women with invasive breast cancer (stages 1 to 4) took the Oncotype DX test. Of those, 16% had a score of less than 11 and were given adjuvant endocrine therapy alone. At five years, the risk of recurrence in this group was less than 2%; overall survival topped 98%.

“Those patients have a very, very low risk of recurring even though they were just treated with surgery, radiation and a hormone,” says Pritchard, who led the trial’s Canadian team. “Many of them [were] patients that we might otherwise have given chemotherapy to because they had large or high-grade tumours.” These results confirm that Oncotype DX is a useful test to give patients to help them decide whether they need adjuvant chemotherapy. In Ontario, the province covers the cost of the test for patients with hormone-sensitive breast cancer. “We will do it if we’re not certain whether to give chemo or not,” says Pritchard.

The TAILORx study is ongoing to determine the outcomes of the 67% of women who had a mid-range score between 11 and 25. These women were randomized to receive either adjuvant endocrine therapy alone or with chemotherapy. The results, expected within two years, will shed light on whether endocrine therapy alone is sufficient to prevent recurrence in patients at intermediate risk.

On the opposite side of the treatment spectrum, Dr. Georg Bjarnason is testing a strategy to address a seldom-recognized problem: underdosing. Bjarnason, a senior scientist at SRI and medical oncologist, focuses on kidney cancer. The standard of care for these patients is an oral drug called sunitinib, which stops tumour growth by staunching the flow of nutrients. “Traditionally, oncologists attempted to give the same dose and schedule of sunitinib to every patient,” says Bjarnason. “It doesn’t make any sense based on what we know about the pharmacology of oral drugs.”

Dr. Georg Bjarnason

Dr. Georg Bjarnason is testing an individualized approach to the oral cancer drug sunitinib. By adjusting the dose and schedule for each patient, he achieved one of the highest response rates for kidney cancer.

While chemotherapy dosing is calculated based on a patient’s height and weight, dosing for oral drugs like sunitinib is fixed at a predetermined level. Sunitinib is typically given at a dose of 50 milligrams per day for 28 days, followed by a two-week break to allow patients to recover from any ill effects. Not everyone, however, endures the same degree of adverse effects. For some, the toxicity is so severe that they cannot complete the full course. Others are able to stay on the drug with minimal discomfort.

In an earlier study, Bjarnason found a correlation between the severity of side effects and a patient’s outcome. “We were the first to observe that in patients with minimum side effects the drug controlled the cancer for a much shorter time,” he says. Patients who required dose and schedule changes to manage adverse effects did much better, suggesting that those who experienced minimal toxicity were, in effect, underdosed. These findings spurred Bjarnason to develop a new strategy. “We hypothesized that we could use toxicity as a surrogate for adequate drug exposure to individualize the therapy for every patient,” he says. With this approach, doctors modified a patient’s dose and schedule such that the level of toxicity was not too much, not too little, but just right.

To evaluate the safety and feasibility of individualized sunitinib treatment, Bjarnason led a Phase 2 trial with 117 participants from 13 centers across Canada. Patients with advanced kidney cancer were started on 50 mg of sunitinib for 28 days. Those unable to tolerate the full dose for 28 days received an individualized lower dose, whereas patients experiencing minimal side effects were given a higher dose. The study is ongoing, but early results show a response rate exceeding 50%, one of the highest reported for advanced kidney cancer. Further, over 90% of patients saw their tumours either stabilize or shrink. “Patients get to take more control of their therapy. They understand that having a bit of toxicity shows that they’re taking an adequately high dose so they accept a degree of toxicity,” says Bjarnason. He hopes these results will give doctors more confidence to individualize and escalate the dose of similar oral cancer drugs if necessary.

Fighting for recognition of a new concept is a struggle that Drs. Edward Chow and Carlo DeAngelis know well. When they first described the phenomenon of pain flare more than 10 years ago, they were met with disbelief. Cancer that has spread to bone can cause debilitating pain. Radiation therapy provides effective relief to patients with agonizing bone metastases. In 30% to 40% of patients, however, radiation therapy induces a temporary worsening of their aches, or a pain flare, in the first week after treatment. “We noticed that for the first few days, we actually made the pain worse,” says Chow, who is a radiation oncologist and senior scientist at SRI. “Everyone else said, ‘No, Edward. You’re just joking.’ People did not believe that.”

It took two studies involving three centres to convince their peers that pain flares were a legitimate—and common—effect of radiotherapy. In a 2009 study led by Chow and DeAngelis, the clinical pharmacy coordinator for oncology at Sunnybrook, patients reported that pain flares interfered with daily activities. Nearly 85% said they would prefer to prevent the pain flare rather than take painkillers, which were often less effective.

A decade after they identified the phenomenon, in 2015, Chow and DeAngelis published results of a Phase 3 trial looking at the effectiveness of dexamethasone in preventing radiation-induced pain flares. Dexamethasone is a corticosteroid used to treat brain tumours, and inflammatory and autoimmune conditions such as rheumatoid arthritis. The drug is cheap—it costs less than 20 cents a pill—and has well-known and minor side effects if used cautiously.

In the study, 298 patients with painful bone metastases were randomly assigned to receive either dexamethasone or a placebo. Patients who received dexamethasone were 9% less likely to experience a pain flare in the first five days after treatment than those who received a placebo. While a reduction of less than 10% might not seem critical, it’s the only treatment that has been shown to have any effect in preventing these flares, says Chow, underscoring the perhaps obvious point that for these patients any difference is welcome. Moreover, the drug reduced pain severity in patients who experienced a flare, and those who took the drug had, on average, less nausea and better appetite. The study was chosen by the Canadian Cancer Society as one of its top 10 research publications of 2015.

“These patients are palliative,” says DeAngelis. “Our best hope is to improve and maintain quality of life for the short period that they have left.” With the next step, he will move into the realm of precision medicine. He will analyze saliva from more than 70 patients in the Phase 3 trial to search for genetic markers that can predict whether a patient will experience a pain flare.

“I call it a neglected cancer with limited treatment options,” says Dr. Simron Singh. “[It’s] a complex disease—hard to understand, hard to treat.” The disease to which he is referring is neuroendocrine cancer, a once-rare condition with one of the fastest rising incidence rates among cancers.

The neuroendocrine system comprises cells that receive instructions from the brain to produce hormones. These cells are distributed throughout the body with high concentrations in the digestive and respiratory systems. When the machinery in these cells runs amok, cancer develops in the form of neuroendocrine tumours (NETs).

Dr. Simron Singh

Dr. Simron Singh talks with his patient Agnes Basemera. Singh is one of the global leads for a trial that showed the drug everolimus cut the risk of disease progression or death in half for patients with neuroendocrine tumours.

Singh is a medical oncologist and co-head of Sunnybrook’s Susan Leslie Clinic for Neuroendocrine Tumours, the largest NET clinic in Canada and one of five major centres in North America. He is also an affiliate scientist at SRI who is the global lead of the gastrointestinal portion of the RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4), an international Phase 3 study on the efficacy and safety of the drug everolimus to treat advanced NETs originating in the lung or gastrointestinal tract. More than 300 patients from 25 countries were randomly assigned to receive either everolimus or a placebo, and then tracked to determine when their cancer progressed.

What the researchers found blew them away. Patients taking everolimus staved off progression for an average of 11 months, whereas those receiving the placebo saw their disease advance in less than four months. Overall, patients who took everolimus were 49% less likely to worsen or die. The impact of delaying disease progression also extended to quality of life. Throughout the trial, patients completed questionnaires that assessed their physical, social, emotional and functional well-being every eight or 12 weeks. The results from these surveys were used to generate a quality of life score. The overall score dropped by nearly five points after the cancer worsened, with the biggest differences seen in physical and functional well-being.

“We imagined it to be a positive trial, but I didn’t anticipate such a dramatic result,” says Singh. The RADIANT-4 study was the largest Phase 3 trial for NETs and the first to identify an effective treatment for patients with advanced NETs originating in the lung. “There was no treatment option before for these particular patients,” he says. “This opened up a new door and hope for them.” The strength of these results convinced the U.S. Food and Drug Administration to approve everolimus as a treatment for advanced NETs. As this story went to press, the drug received approval from Health Canada, and new results from the second interim overall survival analysis were released at the annual meeting of the American Society of Clinical Oncology. These data showed that the estimated two-year survival rate for patients on everolimus was 77% compared to 62% for patients taking the placebo.

When the trial is done, the results analyzed and the papers published, it’s easy to file everything away and move on. Not so for Dr. Laurence Klotz, who is turning to old data to answer new questions. Klotz is a researcher at SRI and a urologist at Sunnybrook. In 2012, he led a landmark study called the PR-7 trial that showed intermittent hormone therapy was as effective as continuous hormone therapy in prolonging survival for men with prostate cancer.

The goal of hormone therapy is to reduce testosterone levels as much as possible so that the hormones cannot stimulate prostate cancer cells to grow. At the time, there were six or seven different drugs used for hormone therapy, with some claiming that they could lower testosterone levels more than others. The key question was, did it matter? Do testosterone levels need to reach a minimum threshold?

“It occurred to me that we had an opportunity with this PR-7 trial,” says Klotz. He revisited the data, focusing on the 626 Canadian patients treated with continuous hormone therapy. During the original study, they collected blood samples from these men to track their testosterone levels over the first year of treatment. In the secondary analysis, Klotz examined how testosterone levels in the first year correlated with long-term outcomes. “To my surprise, it vindicated the hypothesis that testosterone mattered,” he says. “The patients whose testosterone was fully suppressed did much better than ones whose testosterone levels were not.”

Men whose testosterone reached an all-time low of less than 0.7 nanomoles per litre (nmol/L) had a significantly lower risk of developing hormone therapy-resistant prostate cancer or dying from the disease than men whose testosterone levels failed to reach that point. “Historically, we didn’t measure testosterone in patients on hormone therapy. The message is that testosterone should be measured frequently,” says Klotz. “If it’s not fully suppressed below 0.7 nmol/L, then do something to suppress it.”

Finding new and better therapies is all well and good, but cancer drugs are notoriously expensive. Cancer Care Ontario estimates that in 2010 to 2011, the New Drug Funding Program and Ontario Drug Benefit program covered more than $430 million in cancer drugs, a figure that does not include money spent by hospitals, individuals or insurance companies. Despite this, most trials do not examine the potential savings associated with a new drug or treatment strategy. The Clinical Trials Group at the National Cancer Institute of Canada is one of the few cancer cooperative groups in the world with a team dedicated to studying the economic impact of new therapies. “In Canada, we have the perspective that it’s very important to do, especially in our current environment where new drugs are coming in at such huge expense for the system,” says Dr. Matthew Cheung, a haematologist and researcher at SRI.

Dr. Matthew Cheung

Dr. Matthew Cheung found that a new chemotherapy regimen for lymphoma is cheaper and leads to better quality of life than the existing treatment.

In an earlier trial, researchers found that a newer regimen known as GDP—gemcitabine, dexamethasone and cisplatin—was as effective as the historical standard DHAP—dexamethasone, cytosine arabinoside and cisplatin—in treating patients with aggressive lymphoma whose cancer had returned after initial therapy. Cheung led a secondary analysis evaluating the costs and benefits associated with each treatment. To calculate the cost of each treatment, the researchers tallied up the expenses at each step along the way. These include costs from drug pricing and administration, staff wages and hospitalizations due to adverse events.

Benefits were measured using questionnaires administered to patients during the trial, taking into account not just how long patients survive on a given therapy, but also whether they’re able to spend less time in the hospital and more time at home doing activities they enjoy. “If one treatment makes a patient live a lot longer, but it causes them to have a poor quality of life and suffer, then it may not offer all the benefits that we would like patients to have,” says Cheung.

Given the similar results obtained for GDP and DHAP in the original trial, Cheung was shocked to see big differences in his study. The average per-patient cost for GDP was nearly $14,500 lower than the cost for DHAP. This was largely due to longer hospital stays for patients on DHAP because of drug administration protocols and increased toxicity, which led to more hospital visits. The reduced toxicity of GDP also led to patients reporting a higher quality of life. “So GDP is actually both beneficial and less costly for the system,” says Cheung. “It’s the best of all worlds.” These results have begun to change practice in Canada. At Sunnybrook, GDP is prescribed as the standard chemotherapy regimen for patients with recurrent aggressive lymphoma.

All clinical trials seek to solve a common riddle: how can we best care for this patient? In some trials, the answer is clear-cut and obvious. Others require a more nuanced interpretation. For the researchers fabricating a treatment plan person by person, each effort is a step closer toward victories big and small—a pain-free month, an extra year of independence or the ultimate reward: a life unburdened by disease.

Weaving it all Together

Research Funding

Bjarnason: Anna-Liisa Farquharson Chair in Renal Cell Cancer Research, Canadian Institutes of Health Research (CIHR) and Pfizer. Cheung: Canadian Cancer Society Research Institute (CCSRI), Eli Lilly Canada and Hoffman-La Roche Limited. Chowand DeAngelis: CCSRI through the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Klotz: CCSRI through NCIC CTG, National Cancer Institute and National Institute of Health Royal Marsden Institute for Cancer Research Biomedical Research Centre. Pritchard: Canadian Cancer Society through NCIC CTG and National